Landscape of TPMT and NUDT15 Pharmacogenetic Variation in a Cohort of Canadian Pediatric Inflammatory Bowel Disease Patients.

BACKGROUND: Patients with inflammatory bowel disease (IBD) exhibit considerable interindividual variability in medication response, highlighting the need for precision medicine approaches to optimize and tailor treatment. Pharmacogenetics (PGx) offers the ability to individualize dosing by examining genetic factors underlying the metabolism of medications such as thiopurines. Pharmacogenetic testing can identify individuals who may be at risk for thiopurine dose-dependent adverse reactions including myelosuppression. We aimed to evaluate PGx variation in genes supported by clinical guidelines that inform dosing of thiopurines and characterize differences in the distribution of actionable PGx variation among diverse ancestral groups. METHODS: Pharmacogenetic variation in TPMT and NUDT15 was captured by genome-wide genotyping of 1083 pediatric IBD patients from a diverse Canadian cohort. Genetic ancestry was inferred using principal component analysis. The proportion of PGx variation and associated metabolizer status phenotypes was compared across 5 genetic ancestral groups within the cohort (Admixed American, African, East Asian, European, and South Asian) and to prior global estimates from corresponding populations. RESULTS: Collectively, 11% of the cohort was categorized as intermediate or poor metabolizers of thiopurines, which would warrant a significant dose reduction or selection of alternate therapy. Clinically actionable variation in TPMT was more prevalent in participants of European and Admixed American/Latino ancestry (8.7% and 7.5%, respectively), whereas variation in NUDT15 was more prevalent in participants of East Asian and Admixed American/Latino ancestry (16% and 15% respectively). CONCLUSIONS: These findings demonstrate the considerable interpopulation variability in PGx variation underlying thiopurine metabolism, which should be factored into testing diverse patient populations.

In a large, pediatric inflammatory bowel disease cohort comprised of 5 genetic ancestry groups, we evaluated the distribution of loss-of-function pharmacogenetic variants in TPMT and NUDT15 and predicted phenotypes (impact on thiopurine metabolism).

ADALIMUMAB VERSUS INFLIXIMAB IN LUMINAL PEDIATRIC CROHN'S DISEASE: COMPARABLE OUTCOMES IN A PROSPECTIVE MULTICENTER COHORT STUDY.

BACKGROUND: This study compared real-world effectiveness between adalimumab (ADA) and infliximab (IFX) in children with Crohn's disease (CD). METHODS: Children enrolled into the prospective Canadian Children Inflammatory Bowel Disease Network (CIDsCaNN) National Inception Cohort between 2014 and 2020 who commenced ADA or IFX as first anti-tumor necrosis factor (antiTNF) agent for luminal CD were included. Multivariate logistic regression modelled the propensity of commencing ADA; propensity score matching was used to match IFX-treated children to ADA-treated children. The primary outcome at one year was steroid-free clinical remission (SFCR). Secondary outcomes at one year were I) combined SFCR and c-reactive protein (CRP) remission; II) treatment intensification; and III) antiTNF durability. Odds ratios (aOR) and hazard ratio (aHR) adjusted for concomitant immunomodulator use with 95% confidence interval (CI) are reported. RESULTS: In the propensity score matched cohort of 147 ADA-treated and 147 IFX-treated children, 92 (63%) ADA- and 87 (59%) IFX-treated children achieved SFCR at one year (aOR: 1.4, 95% CI 0.9-2.4); 75 of 140 (54%) ADA- and 85 of 144 (59%) IFX-treated children achieved combined SFCR and CRP remission (aOR: 1.0, 95% CI 0.6-1.6). ADA-treated children less frequently underwent treatment intensification (21 [14%]) compared to IFX-treated children (69 [47%]) (P<0.0001). Discontinuation of antiTNF occurred in 18 (12%) ADA-treated and 15 (10%) IFX-treated children (aHR: 1.2, 95% CI 0.6-2.2). CONCLUSION: Children with Crohn's disease achieved favourable outcomes at one year with either ADA or IFX as first antiTNF agents. Those receiving IFX did not have significantly superior outcomes compared to clinically similar children receiving ADA.

Advances in Endoscopy for Pediatric Inflammatory Bowel Disease.

Endoscopic characterization of pediatric inflammatory bowel disease (IBD) has developed in accordance with advances in treatment and improved understanding of disease progression and complications. Reliable and consistent endoscopic reporting practices and tools continue to evolve. The roles of endoscopic ultrasonography, capsule endoscopy, and deep enteroscopy in the care of children and adolescents with IBD are beginning to be clarified. Opportunities for therapeutic intervention with endoscopy in pediatric IBD, including endoscopic balloon dilation and electroincision therapy, require further study. This review discusses the current utility of endoscopic assessment in Pediatric Inflammatory Bowel Disease, as well as emerging and evolving techniques to improve patient care.

Canadian Association of Gastroenterology Clinical Practice Guideline for Immunizations in Patients With Inflammatory Bowel Disease (IBD)-Part 2: Inactivated Vaccines.

BACKGROUND AND AIMS: The effectiveness and safety of vaccinations can be altered by immunosuppressive therapies, and perhaps by inflammatory bowel disease (IBD) itself. These recommendations developed by the Canadian Association of Gastroenterology and endorsed by the American Gastroenterological Association, aim to provide guidance on immunizations in adult and pediatric patients with IBD. This publication focused on inactivated vaccines. METHODS: Systematic reviews evaluating the efficacy, effectiveness, and safety of vaccines in patients with IBD, other immune-mediated inflammatory diseases, and the general population were performed. Critical outcomes included mortality, vaccine-preventable diseases, and serious adverse events. Immunogenicity was considered a surrogate outcome for vaccine efficacy. Certainty of evidence and strength of recommendations were rated according to the GRADE (Grading of Recommendation Assessment, Development, and Evaluation) approach. Key questions were developed through an iterative online platform, and voted on by a multidisciplinary group. Recommendations were formulated using the Evidence-to-Decision framework. Strong recommendation means that most patients should receive the recommended course of action, whereas a conditional recommendation means that different choices will be appropriate for different patients. RESULTS: Consensus was reached on 15 of 20 questions. Recommendations address the following vaccines: Haemophilus influenzae type b, recombinant zoster, hepatitis B, influenza, pneumococcus, meningococcus, tetanus-diphtheria-pertussis, and human papillomavirus. Most of the recommendations for patients with IBD are congruent with the current Centers for Disease Control and Prevention and Canada's National Advisory Committee on Immunization recommendations for the general population, with the following exceptions. In patients with IBD, the panel suggested Haemophilus influenzae type b vaccine for patients older than 5 years of age, recombinant zoster vaccine for adults younger than 50 year of age, and hepatitis B vaccine for adults without a risk factor. Consensus was not reached, and recommendations were not made for 5 statements, due largely to lack of evidence, including double-dose hepatitis B vaccine, timing of influenza immunization in patients on biologics, pneumococcal and meningococcal vaccines in adult patients without risk factors, and human papillomavirus vaccine in patients aged 27-45 years. CONCLUSIONS: Patients with IBD may be at increased risk of some vaccine-preventable diseases. Therefore, maintaining appropriate vaccination status in these patients is critical to optimize patient outcomes. In general, IBD is not a contraindication to the use of inactivated vaccines, but immunosuppressive therapy may reduce vaccine responses.

Prospective Evaluation of Endoscopic and Histologic Indices in Pediatric Ulcerative Colitis Using Centralized Review.

INTRODUCTION: We aimed to evaluate the reliability and validity of the Ulcerative Colitis (UC) Endoscopic Index of Severity (UCEIS) and Mayo Endoscopy Score (MES) and to validate the Robarts Histopathology Index (RHI) and Nancy Index (NI) in pediatric UC. We examined rectosigmoid and pancolonic versions of each instrument. METHODS: Single-center cross-sectional study of 60 prospectively enrolled participants. Through central endoscopy review, 4 pediatric gastroenterologists assigned rectosigmoid and pancolonic (mean of 5 colonic segments) UCEIS and MES scores. Two blinded pathologists assigned rectosigmoid and pancolonic RHI and NI scores. We assessed reliability with intraclass correlation coefficients and weighted kappa statistics and explored construct validity with correlations, boxplots, and receiver operator characteristic curves. RESULTS: The UCEIS and MES displayed almost perfect intra-rater and inter-rater reliability (intraclass correlation coefficient and weighted kappa ≥0.85), moderate-to-strong correlation with histologic/clinical activity and fecal calprotectin (FC), and very strong correlation with global endoscopic severity (r > 0.9). Rectosigmoid UCEIS and MES scores of 0 were highly specific (≥95%) for endoscopic and histologic remission throughout the colon. Pancolonic endoscopy scores correlated more strongly with histologic activity, clinical activity, and systemic inflammatory markers and better discriminated between degrees of active disease. RHI and NI showed moderate-to-strong correlation (r = 0.5-0.83) with endoscopic/clinical activity and FC. DISCUSSION: Our findings support the reliability and construct validity of the UCEIS and MES and the construct validity of the RHI and NI in pediatric UC. Normal rectosigmoid findings predicted pancolonic healing, but, given active disease, pancolonic endoscopic assessment more accurately captured global disease burden.

Canadian Association of Gastroenterology Clinical Practice Guideline for Immunizations in Patients With Inflammatory Bowel Disease (IBD)-Part 2: Inactivated Vaccines.

BACKGROUND AND AIMS: The effectiveness and safety of vaccinations can be altered by immunosuppressive therapies, and perhaps by inflammatory bowel disease (IBD) itself. These recommendations developed by the Canadian Association of Gastroenterology and endorsed by the American Gastroenterological Association, aim to provide guidance on immunizations in adult and pediatric patients with IBD. This publication focused on inactivated vaccines. METHODS: Systematic reviews evaluating the efficacy, effectiveness, and safety of vaccines in patients with IBD, other immune-mediated inflammatory diseases, and the general population were performed. Critical outcomes included mortality, vaccine-preventable diseases, and serious adverse events. Immunogenicity was considered a surrogate outcome for vaccine efficacy. Certainty of evidence and strength of recommendations were rated according to the GRADE (Grading of Recommendation Assessment, Development, and Evaluation) approach. Key questions were developed through an iterative online platform, and voted on by a multidisciplinary group. Recommendations were formulated using the Evidence-to-Decision framework. Strong recommendation means that most patients should receive the recommended course of action, whereas a conditional recommendation means that different choices will be appropriate for different patients. RESULTS: Consensus was reached on 15 of 20 questions. Recommendations address the following vaccines: Haemophilus influenzae type b, recombinant zoster, hepatitis B, influenza, pneumococcus, meningococcus, tetanus-diphtheria-pertussis, and human papillomavirus. Most of the recommendations for patients with IBD are congruent with the current Centers for Disease Control and Prevention and Canada's National Advisory Committee on Immunization recommendations for the general population, with the following exceptions. In patients with IBD, the panel suggested Haemophilus influenzae type b vaccine for patients older than 5 years of age, recombinant zoster vaccine for adults younger than 50 year of age, and hepatitis B vaccine for adults without a risk factor. Consensus was not reached, and recommendations were not made for 5 statements, due largely to lack of evidence, including double-dose hepatitis B vaccine, timing of influenza immunization in patients on biologics, pneumococcal and meningococcal vaccines in adult patients without risk factors, and human papillomavirus vaccine in patients aged 27-45 years. CONCLUSIONS: Patients with IBD may be at increased risk of some vaccine-preventable diseases. Therefore, maintaining appropriate vaccination status in these patients is critical to optimize patient outcomes. In general, IBD is not a contraindication to the use of inactivated vaccines, but immunosuppressive therapy may reduce vaccine responses.

One-year outcomes with ustekinumab therapy in infliximab-refractory paediatric ulcerative colitis: a multicentre prospective study.

BACKGROUND: The phase 3 (UNIFI) trial of ustekinumab (anti-interleukin 12/23) demonstrated efficacy even after prior biologic failure in adult ulcerative colitis (UC), but paediatric data are lacking. AIM: To prospectively monitor efficacy and serum concentrations of ustekinumab given to children with UC refractory to other biologics. METHODS: Children with anti-TNF refractory UC initiating ustekinumab intravenously at sites of the Canadian Children IBD Network prior to 12/2019 are included. The primary endpoint was steroid-free clinical remission with subcutaneous ustekinumab at 52 weeks (Paediatric Ulcerative Colitis Activity Index <10, no steroids ≥4 weeks). Ustekinumab levels were measured after week 20. Endoscopic improvement was defined as Mayo endoscopic subscore ≤1, or faecal calprotectin (FCP) <250 µg/g if not re-colonoscoped. RESULTS: At six sites between 01/2018 and 11/2019, 25 children (median [IQR] age 14.8 years [12.3-16.2], 72% female) with UC duration 2.3 years (1.1-4.2) received intravenous ustekinumab (median dose/kg of 6.4 [5.5-7.5] mg). All patients had failed prior infliximab therapy, and 12 (48%) also vedolizumab. Five patients discontinued ustekinumab after IV induction (four undergoing colectomy). On intent to treat basis, 44% achieved the primary endpoint of steroid-free remission at week 52, including nine (69%) of 13 who previously treated with anti-TNF only vs two (17%) of 12 who previously failed also by vedolizumab (P = 0.008). Seven of 11 remitters met the criteria for endoscopic improvement. The median (IQR) trough levels (µg/mL) were greater with q4 vs q8 weekly dosing (8.7 [4.6-9.9] vs 3.8 [12.7-4.8]) P = 0.02, but greater exposure was not associated with a superior rate of clinical remission. No adverse events were associated with therapy. CONCLUSION: Ustekinumab demonstrated efficacy in this paediatric cohort with otherwise treatment-refractory UC. Treatment failure was not due to inadequate drug exposure.

Predicting Outcomes in Pediatric Crohn's Disease for Management Optimization: Systematic Review and Consensus Statements From the Pediatric Inflammatory Bowel Disease-Ahead Program.

BACKGROUND & AIMS: A better understanding of prognostic factors within the heterogeneous spectrum of pediatric Crohn's disease (CD) should improve patient management and reduce complications. We aimed to identify evidence-based predictors of outcomes with the goal of optimizing individual patient management. METHODS: A survey of 202 experts in pediatric CD identified and prioritized adverse outcomes to be avoided. A systematic review of the literature with meta-analysis, when possible, was performed to identify clinical studies that investigated predictors of these outcomes. Multiple national and international face-to-face meetings were held to draft consensus statements based on the published evidence. RESULTS: Consensus was reached on 27 statements regarding prognostic factors for surgery, complications, chronically active pediatric CD, and hospitalization. Prognostic factors for surgery included CD diagnosis during adolescence, growth impairment, NOD2/CARD15 polymorphisms, disease behavior, and positive anti-Saccharomyces cerevisiae antibody status. Isolated colonic disease was associated with fewer surgeries. Older age at presentation, small bowel disease, serology (anti-Saccharomyces cerevisiae antibody, antiflagellin, and OmpC), NOD2/CARD15 polymorphisms, perianal disease, and ethnicity were risk factors for penetrating (B3) and/or stenotic disease (B2). Male sex, young age at onset, small bowel disease, more active disease, and diagnostic delay may be associated with growth impairment. Malnutrition and higher disease activity were associated with reduced bone density. CONCLUSIONS: These evidence-based consensus statements offer insight into predictors of poor outcomes in pediatric CD and are valuable when developing treatment algorithms and planning future studies. Targeted longitudinal studies are needed to further characterize prognostic factors in pediatric CD and to evaluate the impact of treatment algorithms tailored to individual patient risk.

Predicting Outcomes in Pediatric Ulcerative Colitis for Management Optimization: Systematic Review and Consensus Statements From the Pediatric Inflammatory Bowel Disease-Ahead Program.

BACKGROUND & AIMS: A better understanding of prognostic factors in ulcerative colitis (UC) could improve patient management and reduce complications. We aimed to identify evidence-based predictors for outcomes in pediatric UC, which may be used to optimize treatment algorithms. METHODS: Potential outcomes worthy of prediction in UC were determined by surveying 202 experts in pediatric UC. A systematic review of the literature, with selected meta-analysis, was performed to identify studies that investigated predictors for these outcomes. Multiple national and international meetings were held to reach consensus on evidence-based statements. RESULTS: Consensus was reached on 31 statements regarding predictors of colectomy, acute severe colitis (ASC), chronically active pediatric UC, cancer and mortality. At diagnosis, disease extent (6 studies, N = 627; P = .035), Pediatric Ulcerative Colitis Activity Index score (4 studies, n = 318; P < .001), hemoglobin, hematocrit, and albumin may predict colectomy. In addition, family history of UC (2 studies, n = 557; P = .0004), extraintestinal manifestations (4 studies, n = 526; P = .048), and disease extension over time may predict colectomy, whereas primary sclerosing cholangitis (PSC) may be protective. Acute severe colitis may be predicted by disease severity at onset and hypoalbuminemia. Higher Pediatric Ulcerative Colitis Activity Index score and C-reactive protein on days 3 and 5 of hospital admission predict failure of intravenous steroids. Risk factors for malignancy included concomitant diagnosis of primary sclerosing cholangitis, longstanding colitis (>10 years), male sex, and younger age at diagnosis. CONCLUSIONS: These evidence-based consensus statements offer predictions to be considered for a personalized medicine approach in treating pediatric UC.

Diagnostic Delay Is Associated With Complicated Disease and Growth Impairment in Paediatric Crohn's Disease.

BACKGROUND: Paediatric data on the association between diagnostic delay and inflammatory bowel disease [IBD] complications are lacking. We aimed to determine the effect of diagnostic delay on stricturing/fistulising complications, surgery, and growth impairment in a large paediatric cohort, and to identify predictors of diagnostic delay. METHODS: We conducted a national, prospective, multicentre IBD inception cohort study including 1399 children. Diagnostic delay was defined as time from symptom onset to diagnosis >75th percentile. Multivariable proportional hazards [PH] regression was used to examine the association between diagnostic delay and stricturing/fistulising complications and surgery, and multivariable linear regression to examine the association between diagnostic delay and growth. Predictors of diagnostic delay were identified using Cox PH regression. RESULTS: Overall (64% Crohn's disease [CD]; 36% ulcerative colitis/IBD unclassified [UC/IBD-U]; 57% male]), median time to diagnosis was 4.2 (interquartile range [IQR] 2.0-9.2) months. For the overall cohort, diagnostic delay was >9.2 months; in CD, >10.8 months and in UC/IBD-U, >6.6 months. In CD, diagnostic delay was associated with a 2.5-fold higher rate of strictures/internal fistulae (hazard ratio [HR] 2.53, 95% confidence interval [CI] 1.41-4.56). Every additional month of diagnostic delay was associated with a decrease in height-for-age z-score of 0.013 standard deviations [95% CI 0.005-0.021]. Associations persisted after adjusting for disease location and therapy. No independent association was observed between diagnostic delay and surgery in CD or UC/IBD-U. Diagnostic delay was more common in CD, particularly small bowel CD. Abdominal pain, including isolated abdominal pain in CD, was associated with diagnostic delay. CONCLUSIONS: Diagnostic delay represents a risk factor for stricturing/internal fistulising complications and growth impairment in paediatric CD. PODCAST: This article has an associated podcast which can be accessed at https://academic.oup.com/ecco-jcc/pages/podcast.

Anticipatory care of children and adolescents with inflammatory bowel disease: a primer for primary care providers.

PURPOSE OF REVIEW: About 10-20% of patients with newly diagnosed inflammatory bowel disease (IBD) are under 18 years of age, with incidence increasing in young children. Children with IBD have unique healthcare needs, which require coordination between primary care providers and pediatric gastroenterologists to provide appropriate care. This review highlights some key elements of anticipatory care in pediatric IBD, including vaccination, risk of serious infection and malignancy, psychosocial and educational needs, and cannabis use. RECENT FINDINGS: Therapies for IBD that include anti-tumor necrosis factor medications, especially when combined with corticosteroids are associated with higher risks of serious infections. Vaccination remains the best way to prevent infections. Live vaccinations should be avoided during immunosuppression, but the schedule should be otherwise completed, including vaccination for influenza, pneumococcus and meningococcus, and human papillomavirus. Malignancy risk is increased in IBD patients, both because of disease factors and resulting from immunomodulatory medications. Children with IBD are at risk for mental health disorders and negative educational outcomes, so identification of at-risk children and early intervention are important. SUMMARY: High-quality care in pediatric IBD requires coordination between pediatric gastroenterologists and primary care providers, with careful attention paid to the specific needs of children with IBD.

The pediatric inflammatory bowel disease INTERMED: A new clinical tool to assess psychosocial needs.

OBJECTIVE: The adult INTERMED is used to determine case complexity and psychosocial needs. We developed and validated a pediatric version of the INTERMED for children and adolescents with inflammatory bowel disease (IBD) and assessed its utility in predicting healthcare utilization. METHODS: We performed a cross-sectional study of children (aged 8-17 y) with IBD (n = 148) and their parents, seen in a hospital-based clinic. Subjects completed semi-structured interviews that were scored on the 34 pIBD-INTERMED items. To assess inter-rater reliability, 40 interviews were videotaped and scored by a second assessor. Convergent and predictive validity were assessed by examining the relation of the pIBD-INTERMED to standardized measures of psychological, social, and family functioning, disease activity, and healthcare utilization. RESULTS: Correlational analyses supported the validity of all five pIBD-INTERMED domains with very good inter-rater reliability (median r = 0.87) and internal consistency (α = 0.91) for the total complexity index. Ratings of 2-3 on the pIBD-INTERMED "mental health/cognitive threat" item were associated with greater odds of behavior and social problems (CBCL-Internalizing scale OR = 7.27, 95% CI 2.17-24.36); CBCL-Externalizing scale OR = 24.79, 95% CI 5.00-122.84), depression (Children's Depression Inventory OR = 8.52, 95% CI 1.70-43.02) and anxiety (Multidimensional Anxiety for Children OR = 11.57, 95% CI 3.00-45.37). The pIBD-INTERMED complexity index added significantly to the prediction of healthcare utilization, beyond the contribution of disease severity. CONCLUSIONS: The pIBD-INTERMED is a reliable and valid tool for identifying psychosocial risks and needs of children with IBD. It can be used to guide planning of individualized care and enhance interdisciplinary pediatric IBD care.

Ferric carboxymaltose in the treatment of iron deficiency in pediatric inflammatory bowel disease.

BACKGROUND: Iron deficiency (ID) with or without anemia is a common complication of pediatric inflammatory bowel disease (IBD), causing significant morbidity. Despite this, ID remains prevalent and undertreated, related in part to questions surrounding optimal formulation and route of administration. Ferric carboxymaltose (FCM) is a recent formulation of intravenous iron, allowing higher doses and rapid infusion times. This study aims to demonstrate the efficacy and safety of FCM in paediatric patients with IBD, and explore the differences between patients with active and quiescent disease. METHODS: Paediatric patients 6-18 years with IBD with iron deficiency (ID) or iron deficiency anemia (IDA) were treated prospectively with FCM at the Queensland Children's Hospital in Brisbane. Patients received FCM as a single dose of 15 mg/kg up to 1,000 mg over 15-20 min. Biochemical parameters measured prior to and approximately 8 weeks after the infusion were: hemoglobin (Hb), mean corpuscular volume (MCV), ferritin, and transferrin saturation (TS). C-reactive protein (CRP) was measured as a marker of co-existing inflammation. Resolution of anemia or ID was assessed following treatment, with adverse events captured. RESULTS: A total of 101 patients received infusions of FCM during the study period and were analysed, median age 14 (IQR 14-16) years. A total of 44% of patients underwent treatment for IDA, while 56% were for ID without anemia. Following FCM infusion, 64% of patients with IDA had resolution of anemia, with 81% showing resolution for ID without anemia. Elevation of CRP throughout the study period had no influence on resolution of IDA with FCM (P=0.68), but in patients with ID, patients with quiescent disease activity were more likely to have resolution of ID [odds ratios (ORs) 5.1; P=0.03]. CONCLUSIONS: Rapid, high dose FCM in children aged 6 and over is safe, well tolerated and efficacious for correction of ID. Replenishing iron in IBD is important and FCM improves our ability to meet this need.

Clinical disease activity and endoscopic severity correlate poorly in children newly diagnosed with Crohn's disease.

BACKGROUND AND AIMS: Treatment goals in Crohn's disease (CD) have evolved to target mucosal healing. There is now a drive to determine if noninvasive measures can adequately identify the attainment and persistence of this goal. Currently, data describing the relationship between clinical indices and endoscopic appearance in pediatric CD are sparse. Our aim was to compare endoscopic severity with the weighted Pediatric Crohn's Disease Activity Index (wPCDAI) in children with newly diagnosed CD. METHODS: All children aged ≤17 years newly diagnosed with CD enrolled in an inception cohort at sites of the Canadian Children Inflammatory Bowel Disease Network were eligible. Clinical disease activity at presentation was evaluated by the wPCDAI and conventional biochemical parameters. Severity of disease at ileocolonoscopy was assessed by the simple endoscopic score for CD (SES-CD), with segmental subscores noted. We evaluated the association of SES-CD and disease activity markers using the Pearson test of correlation, the Spearman rank coefficient, and linear regression models. RESULTS: Two hundred eighty patients from 11 centers were included in the analysis. The median wPCDAI score was 60 (interquartile range, 40-80; 53% severe). Median SES-CD was 16 (interquartile range 10-22; 51% severe). The wPCDAI correlated weakly with SES-CD (r = .39, P < .001). Examination of the individual components that contribute to the wPCDAI demonstrated weak correlation with the SES-CD for all items apart from stooling (moderate correlation, r = .50, P < .001). Routine blood tests did not correlate well with the SES-CD. In regression models, variation in clinical symptoms accounted for most of the variation in both the wPCDAI and SES-CD, with no additional benefit from routine blood tests. CONCLUSIONS: In children with newly diagnosed CD, wPCDAI correlates poorly with endoscopic disease activity. As treatment paradigms evolve to target mucosal healing, clinical markers should not be used in isolation to determine disease activity.

Therapeutic Drug Monitoring in Pediatric Inflammatory Bowel Disease.

PURPOSE OF REVIEW: Therapeutic drug monitoring (TDM) has emerged as a useful tool to optimize the use of drug therapies in adults with inflammatory bowel disease (IBD), including both Crohn's disease (CD) and ulcerative colitis (UC), especially during the use of biological therapies, for which the pharmacokinetics and pharmacodynamics are highly variable among patients. Fewer data exist in children. This review examines the current literature on TDM in pediatric IBD. RECENT FINDINGS: Drug clearance is affected by a number of patient and disease factors. For thiopurines, adjusting dosing by monitoring 6-thioguanine (6TGN) and 6-methylmercaptopurine ((6MMP) levels is demonstrated to maximize response and minimize toxicity, while monitoring metabolite levels when treating with anti-tumor necrosis factor (anti-TNF) remain controversial. While in adults the use of TDM in the setting of loss of response to anti-TNF therapy is established, in children, only a small number of studies exist, but these too have encouraging results. There are however, conflicting data regarding the optimal timing of TDM, comparing "reactive" monitoring and "proactive" monitoring. No such data exist in pediatrics. TDM is cost-effective, and dose reduction may represent a safety benefit. There are limited adult data for use of TDM for the newer biologics, vedolizumab and ustekinumab, but early results suggest similarly promising utility. The use of TDM in pediatric IBD is increasing in clinical practice, with similar efficacy to adults demonstrated in children with loss of response to anti-TNF therapy. More prospective studies are needed in children to examine proactive monitoring and utility of TDM with newer biologics.

Symptoms Do Not Correlate With Findings From Colonoscopy in Children With Inflammatory Bowel Disease and Primary Sclerosing Cholangitis.

BACKGROUND & AIMS: Approximately 75% of children with primary sclerosing cholangitis (PSC) also have inflammatory bowel disease (IBD). IBD in patients with PSC (PSC-IBD) often has a unique phenotype, including a mild clinical course, yet it is associated with an increased risk of colorectal cancer compared with colonic IBD without PSC. We investigated whether subclinical endoscopic and histologic inflammation could account for the increased risk of colorectal cancer in patients with PSC-IBD, and whether these patients have increased fecal levels of calprotectin, a marker of inflammation. METHODS: We performed a prospective study of children (age, <18 y) with colonic IBD with and without PSC who underwent colonoscopy from February 1, 2016, through March 31, 2017, at the Hospital for Sick Children in Toronto, Canada. We collected pediatric ulcerative colitis activity index (PUCAI) scores (to measure symptoms) and fecal levels of calprotectin from 37 children with PSC-IBD and 50 children with only IBD (controls; UC or IBD-unclassified). Colonoscopies were scored using the Mayo endoscopic subscore and the UC Endoscopic Index of Severity (UCEIS) scores, and histologic activity was graded. Among patients in clinical remission, endoscopic scores and the odds of active endoscopic disease (based on a UCEIS score ≥1) were compared between patients with and without PSC in univariate and multivariable analyses. Correlations between activity markers were compared between groups. The ability of fecal calprotectin to identify mucosal healing in patients with PSC-IBD was assessed using receiver operating characteristic curve analyses. Analogous analyses were performed for histologic activity. RESULTS: Patients with PSC-IBD in clinical remission had higher endoscopic scores and greater odds of active endoscopic disease than controls (odds ratio, 5.9; 95% CI, 1.6-21.5). There was a higher degree of correlation between PUCAI and UCEIS scores in controls (r = 0.82) than in patients with PSC-IBD (r = 0.51; P = .01). Fecal levels of calprotectin correlated with UCEIS in patients with PSC-IBD (r = 0.84) and controls (r = 0.82; P = .80). Fecal levels of calprotectin identified mucosal healing in patients with PSC-IBD with an area under the receiver operating characteristic curve of 0.94 (optimal cut-point, 93 µg/g; 100% sensitivity and 92% specificity). Histologic activity scores and the odds of active histologic disease were also greater in patients in clinical remission with PSC-IBD than controls. CONCLUSIONS: Children with PSC-IBD in clinical remission, based on PUCAI scores, have a significantly higher risk of active endoscopic and histologic disease than children with colitis without PSC. Fecal levels of calprotectin correlate with endoscopic findings in pediatric patients with PSC-IBD; levels below 93 µg/g are associated with mucosal healing.

Diagnostic delay in Canadian children with inflammatory bowel disease is more common in Crohn's disease and associated with decreased height.

OBJECTIVES: To determine time to diagnosis in a paediatric inflammatory bowel disease (IBD) cohort and the relative contribution of the component intervals, and to identify factors associated with diagnostic delay. DESIGN: Prospective cohort study SETTING: Single-centre study including children with incident IBD at the Hospital for Sick Children diagnosed between December 2013 and December 2015. INTERVENTIONS: Time to diagnosis and its subintervals were determined and patient, disease and institutional factors were tested for associations. RESULTS: Among 111 children, the median overall time to diagnosis was 4.5 (IQR 2.1-8.8) months. Time to diagnosis was longer in Crohn's disease (CD) than ulcerative colitis (UC) (median 6.8 (IQR 2.9-12.5) vs 2.4 (IQR 1.3-5.3) months) and patients with isolated small bowel disease. Twenty per cent of patients were diagnosed≥1 year after symptom onset (86% CD, 14% UC, p=0.003). Time from symptom onset to gastroenterology referral was the greatest contributor to overall time to diagnosis (median 2.9 (IQR 1.6-8.2) months). Height impairment was independently associated with diagnostic delay (OR 0.59, p=0.02, for height-for-age z-score (HAZ), signifying almost 70% increased odds of delay for every 1 SD decrease in HAZ). This height discrepancy persisted 1 year after diagnosis. Bloody diarrhoea was protective against delay (OR 0.28, p=0.02). The subinterval from referral to diagnosis was shorter in patients with laboratory abnormalities, particularly hypoalbuminaemia. CONCLUSIONS: Diagnostic delay was more common in CD and associated with height impairment that persisted 1 year after presentation. The greatest contributor to time to diagnosis was time from symptom onset to referral.

New Onset Autoimmune Hepatitis during Anti-Tumor Necrosis Factor-Alpha Treatment in Children.

OBJECTIVES: To evaluate a large anti-tumor necrosis factor (TNF)-treated pediatric inflammatory bowel disease cohort for drug-induced liver injury (DILI) following presentation of an index case with suspected DILI with autoimmune features after infliximab exposure. To characterize the incidence, natural history, and risk factors for liver enzyme elevation with anti-TNF use. STUDY DESIGN: We reviewed the index case and performed a retrospective cohort study of 659 children receiving anti-TNF therapy between 2000 and 2015 at a tertiary pediatric inflammatory bowel disease center. Patients with alanine aminotransferase (ALT) ≥×2 the upper limit of normal were included. The incidence, evolution, and risk factors for liver injury were examined with univariate and multivariable proportional hazards regression. Causality was assessed using the Roussel-Uclaf Causality Assessment Method. RESULTS: The index case, a teenage girl with Crohn's disease, developed elevated liver enzymes and features of autoimmune hepatitis on liver biopsy 23 weeks after starting infliximab. The injury resolved entirely within 4 months of withdrawing infliximab without additional therapy. Overall, 7.7% of our cohort developed new ALT elevations while on anti-TNF. Most ALT elevations were mild and transient and attributable to alternate etiologies. No additional clear cases of autoimmune hepatitis were identified. CONCLUSIONS: Transient liver enzyme abnormalities are relatively common among anti-TNF-treated children. Anti-TNF-related DILI with autoimmune features is rare but must be recognized so that therapy can be stopped.

Can MR enterography screen for perianal disease in pediatric inflammatory bowel disease?

BACKGROUND: Pediatric Crohn's disease is associated with perianal disease (PAD). Magnetic resonance enterography (MRE) assesses small bowel involvement in pediatric inflammatory bowel disease (PIBD). Pelvic MRI (P-MRI) is the gold standard for assessing PAD. PURPOSE: To determine if MRE can accurately detect PAD in PIBD, distinguishing perianal fistulae (PAF) from perianal abscesses (PAA), referenced against P-MRI. STUDY TYPE: Retrospective. POPULATION: Seventy-seven PIBD patients, 27 females (mean age 14.1 years), with P-MRI and MRE within 6 months. FIELD STRENGTH/SEQUENCE: 1.5T and 3T; P-MRI: sagittal fat suppressed (FS) T2 fast spin-echo (FSE), coronal short tau inversion recovery, axial T1 FSE, coronal and axial postcontrast FS T1 FSE; MRE: coronal balanced steady-state free-precession (SSFP), coronal cine SSFP, coronal and axial single-shot T2 FS, axial SSFP, coronal ultrafast 3D T1 -weighted gradient echo FS (3D T1 GE), axial diffusion-weighted imaging, coronal and axial postcontrast 3D T1 GE FS. ASSESSMENT: Two radiologists independently, then by consensus, assessed randomized MRI exams, recording PAF number, location, and length; and PAA number, location, length, and volume. Sensitivity analysis used clinical disease as the gold standard, calculated separately for P-MRI and MRE. STATISTICAL TESTS: Comparing MRE and P-MRI consensus data, sensitivity, specificity, positive, and negative predictive values (P/NPV) were calculated. Inter- and intrareader reliability were assessed using kappa statistics. RESULTS: P-MRI and MRE were paired, detecting PAD in 73 patients, PAF in 63, and PAA in 31 P-MRI. MRE sensitivities, specificities, PPV, and NPV were: PAD 82%, 100%, 100%, 23%; PAF 74%, 71%, 92%, 38%; PAA 51%, 85%, 69%, 72%; clinical 82%, 22%, 37%, 69%; clinical P-MRI 96%, 8%, 37%, 80%. MRE interreader agreement for PAD was moderate (kappa = 0.51 [0.29-0.73]), fair for PAF and PAA. DATA CONCLUSION: Using a standard technique, MRE can detect PAD with high specificity and moderate sensitivity in PIBD, missing some PAF and small PAA. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1638-1645.

Pulse wave velocity measurement as a marker of arterial stiffness in pediatric inflammatory bowel disease: a pilot study.

In adults with inflammatory bowel disease (IBD), the incidence of cardiovascular events is increased, leading to long-term morbidity. Arterial stiffness (AS) measured by pulse wave velocity (PWV) is a validated early precursor of cardiovascular disease (CVD), and measurement of PWV was shown to be a feasible test in children. The aim of this study was to assess AS in children with IBD. In this prospective study, we determined PWV between the carotid and femoral artery (PWVcf) in 25 children and adolescents with IBD (11 females, median age 14.1 years, median disease duration 2.8 years). The majority (68%) of the subjects were in clinical remission, and 48% received anti-tumor necrosis factor alpha (TNFα) treatment. AS was not increased in this cohort of children and adolescents with IBD, who did not have signs of cardiovascular disease, such as arterial hypertension. CONCLUSION: PWV seems to be normal in children with IBD in remission or with mild disease activity. Larger studies should assess its potential role as a valid and non-invasive follow-up marker in children with IBD, to avoid cardiovascular complications. What is Known : • Inflammatory bowel disease (IBD) is a risk factor of cardiovascular disease (CVD). • Pulse wave velocity (PWV) measurement is the current gold standard to assess arterial stiffness (AS), which is an early predictor of CVD. What is New: • This is the first study using PWV measurements to determine AS in children with IBD. • In children with IBD in remission or only mild disease activity AS is not increased.